Genetic liability, prenatal health, stress and family environment: Risk factors in the Harvard Adolescent Family High Risk for Schizophrenia Study Deborah J. Walder a,b,c, ⁎, Stephen V. Faraone d,e , Stephen J. Glatt d,e , Ming T. Tsuang f,g , Larry J. Seidman c,h, ⁎⁎ a Brooklyn College, Department of Psychology, United States b The Graduate Center of The City University of New York (CUNY), United States c Harvard Medical School, Department of Psychiatry at Beth Israel Deaconess Medical Center, United States d SUNY Upstate Medical University, Department of Psychiatry and Behavioral Sciences, United States e SUNY Upstate Medical University, Center for Neuropsychiatric Genetics, Biomedical Sciences Program, Neuroscience and Physiology, United States f Center for Behavioral Genomics and Institute of Genomic Medicine, Department of Psychiatry at University of California — San Diego, United States g Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard School of Public Health, United States h Harvard Medical School, Department of Psychiatry at Massachusetts General Hospital, United States abstract article info Article history: Received 8 January 2014 Received in revised form 6 April 2014 Accepted 11 April 2014 Available online 16 May 2014 Keywords: Stress Psychosis Relatives Obstetric complications Neurodevelopment Family environment Objectives: The familial (“genetic”) high-risk (FHR) paradigm enables assessment of individuals at risk for schizo- phrenia based on a positive family history of schizophrenia in first-degree, biological relatives. This strategy presumes genetic transmission of abnormal traits given high heritability of the illness. It is plausible, however, that adverse environmental factors are also transmitted in these families. Few studies have evaluated both bio- logical and environmental factors within a FHR study of adolescents. Methods: We conceptualize four precursors to psychosis pathogenesis: two biological (genetic predisposition, prenatal health issues (PHIs)) and two environmental (family environment, stressful life events (SLEs)). Partic- ipants assessed between 1998 and 2007 (ages 13–25) included 40 (20F/20M) adolescents at FHR for schizophre- nia (FHRs) and 55 (31F/24M) community controls. ‘Genetic load’ indexed number of affected family members relative to pedigree size. Results: PHI was significantly greater among FHRs, and family cohesion and expressiveness were less (and family conflict was higher) among FHRs; however, groups did not significantly differ in SLE indices. Among FHRs, genet- ic liability was significantly associated with PHI and family expressiveness. Conclusions: Prenatal and family environmental disruptions are elevated in families with a first-degree relative with schizophrenia. Findings support our proposed ‘polygenic neurodevelopmental diathesis–stress model’ whereby psychosis susceptibility (and resilience) involves the independent and synergistic confluence of (temporally-sensitive) biological and environmental factors across development. Recognition of biological and social environmental influences across critical developmental periods points to key issues relevant for enhanced identification of psychosis susceptibility, facilitation of more precise models of illness risk, and development of novel prevention strategies. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Over the last few decades it has become firmly established that schizo- phrenia has early neurodevelopmental origins (Lewis and Murray, 1987; Weinberger, 1987) that later manifest in illness expression through disruptions of normal neuromaturational processes (Walker and Bollini, 2002). Biological susceptibility is reflected in 1) behavioral (fam- ily, twin, adoption) genetic studies yielding heritability estimates of approximately .65–.70 (Gottesman and Shields, 1967), confirmed by na- tional population-based and registry studies in Denmark (Wray and Gottesman, 2012) and Sweden (Lichtenstein et al., 2009) and 2) elevated rates of perinatal complications in schizophrenia (Cannon, Jones et al., 2002; Cannon, van Erp et al., 2002). Increasingly, molecular genetic ori- gins are being tested with large-scale consortia (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013), pointing to complex polygenic influences involving many common single nucleotide variants and rare events such as copy number variants. Perinatal complications Schizophrenia Research 157 (2014) 142–148 ⁎ Correspondence to: D.J. Walder, Department of Psychology, Rm 5315 James Hall, Brooklyn College, 2900 Bedford Avenue, Brooklyn, NY 11210, United States. Tel.: +1 718 951 5000; fax: +1 718 951 4814. ⁎⁎ Correspondence to: L.J. Seidman, Massachusetts Mental Health Center, 75 Fenwood Road, Boston, MA 02115, United States. Tel.: +1 617 754 1238; fax: +1 617 754 1250. E-mail addresses: DWalder@brooklyn.cuny.edu (D.J. Walder), lseidman@bidmc.harvard.edu (L.J. Seidman). http://dx.doi.org/10.1016/j.schres.2014.04.015 0920-9964/© 2014 Elsevier B.V. All rights reserved. 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